Caspofungin Acetate

1 INDICATIONS AND USAGE Caspofungin acetate for Injection is an echinocandin antifungal indicated in adults and pediatric patients (3 months of age and older) for: • Empirical therapy for presumed fungal infections in febrile, neutropenic patients. ( 1 ) • Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. ( 1 ) • Treatment of esophageal candidiasis. ( 1 ) • Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies. ( 1 ) 1.1 Empirical Therapy for Presumed Fungal Infections in Febrile, Neutropenic Patients Caspofungin acetate for Injection is indicated as empirical therapy for presumed fungal infections in febrile, neutropenic adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.1 , 14.5 )] . 1.2 Treatment of Candidemia and Other Candida Infections Caspofungin acetate for Injection is indicated for the treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.2 , 14.5 )] . Limitations of Use: Caspofungin acetate for Injection has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida . 1.3 Treatment of Esophageal Candidiasis Caspofungin acetate for Injection is indicated for the treatment of esophageal candidiasis in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.3 , 14.5 )]. Limitations of Use: Caspofungin acetate for Injection has not been approved for the treatment of oropharyngeal candidiasis (OPC). In the study that evaluated the efficacy of caspofungin in the treatment of esophageal candidiasis, patients with concomitant OPC had higher relapse rate of the OPC [see Clinical Studies ( 14.3 )] . 1.4 Treatment of Invasive Aspergillosis in Patients Who Are Refractory to or Intolerant of Other Therapies Caspofungin acetate for Injection is indicated for the treatment of invasive aspergillosis in adult and pediatric patients (3 months of age and older) who are refractory to or intolerant of other therapies [see Clinical Studies ( 14.4 , 14.5 )] . Limitations of Use: Caspofungin acetate for Injection has not been studied as initial therapy for invasive aspergillosis.

2 DOSAGE AND ADMINISTRATION Important Administration Instructions for All Patients ( 2.1 ): • Administer by slow intravenous (IV) infusion over approximately 1 hour. Do not administer by intravenous (IV) bolus administration. • Do not mix or co-infuse Caspofungin acetate for Injection with other medications. Do not use diluents containing dextrose (α- D-glucose). Dosage in Adults [18 years of age and older] ( 2.2 ): • Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily for all indications except esophageal candidiasis. • For esophageal candidiasis, use 50 mg once daily with no loading dose. Dosage in Pediatric Patients [3 months to 17 years of age] ( 2.3 ) : • Dosing should be based on the patient's body surface area. • For all indications, administer a single 70 mg/m2 loading dose on Day 1, followed by 50 mg/m2 once daily thereafter. • Maximum loading dose and daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. Dosage Adjustments in Patients with Hepatic Impairment ( 2.4 ): Reduce dosage for adult patients with moderate hepatic impairment (35 mg once daily, with a 70 mg loading dose on Day 1 where appropriate). Dosage Adjustments in Patients Receiving Concomitant Inducers of Hepatic CYP Enzymes ( 2.5 ): • Use 70 mg once daily dose for adult patients on rifampin. • Consider dose increase to 70 mg once daily for adult patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin. • Pediatric patients receiving these same concomitant medications may also require an increase in dose to 70 mg/m2 once daily (maximum daily dose not to exceed 70 mg). 2.1 Important Administration Instructions for Use in All Patients Administer Caspofungin acetate for Injection by slow intravenous (IV) infusion over approximately 1 hour. Do not administer Caspofungin acetate for Injection by intravenous (IV) bolus administration. 2.2 Recommended Dosage in Adult Patients [18 years of age and older] The dosage and duration of Caspofungin acetate for Injection treatment for each indication are as follows: Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient's clinical response. Continue empirical therapy until resolution of neutropenia. In general, treat patients found to have a fungal infection for a minimum of 14 days after the last positive culture and continue treatment for at least 7 days after both neutropenia and clinical symptoms are resolved. If the 50 mg dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg. Candidemia and Other Candida Infections Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be dictated by the patient's clinical and microbiological response. In general, continue antifungal therapy for at least 14 days after the last positive culture. Patients with neutropenia who remain persistently neutropenic may warrant a longer course of therapy pending resolution of the neutropenia. Esophageal Candidiasis The dose is 50 mg once daily for 7 to 14 days after symptom resolution. A 70 mg loading dose has not been studied for this indication. Because of the risk of relapse of oropharyngeal candidiasis in patients with HIV infections, suppressive oral therapy could be considered [see Clinical Studies ( 14.3 )]. Invasive Aspergillosis Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. 2.3 Recommended Dosing in Pediatric Patients [3 months to 17 years of age] For all indications, administer a single 70 mg/m 2 loading dose on Day 1, followed by 50 mg/m 2 once daily thereafter. The m…

5 WARNINGS AND PRECAUTIONS • Hypersensitivity : Anaphylaxis, possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm, and cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with use of caspofungin acetate for injection. Discontinue Caspofungin acetate for Injection at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment. ( 5.1 ) • Hepatic Effects : Can cause abnormalities in liver enzymes. Isolated cases of hepatic dysfunction, hepatitis, or hepatic failure have been reported. Monitor patients who develop abnormal liver enzymes for evidence of worsening hepatic function and evaluate risk/benefit of continuing Caspofungin acetate for Injection. ( 5.2 ) • Elevated Liver Enzymes during Concomitant use with Cyclosporine: Limit use to patients for whom potential benefit outweighs potential risk. Monitor patients who develop abnormal liver function tests (LFTs) during concomitant use with Caspofungin acetate for Injection. ( 5.3 ) 5.1 Hypersensitivity Anaphylaxis and other hypersensitivity reactions have been reported during administration of caspofungin acetate for injection. Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with use of caspofungin acetate for injection [see Adverse Reactions ( 6.2 )] . Discontinue Caspofungin acetate for Injection at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment. 5.2 Hepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with caspofungin acetate for injection. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin acetate for injection, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to caspofungin acetate for injection has not been established. Monitor patients who develop abnormal liver function tests during Caspofungin acetate for Injection therapy for evidence of worsening hepatic function and evaluated for risk/benefit of continuing Caspofungin acetate for Injection therapy. 5.3 Elevated Liver Enzymes During Concomitant Use with Cyclosporine Elevated liver enzymes have occurred in patients receiving caspofungin acetate for injection and cyclosporine concomitantly. Only use Caspofungin acetate for Injection and cyclosporine in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver enzymes during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated.

4 CONTRAINDICATIONS Caspofungin acetate for Injection is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to any component of this product [see Adverse Reactions ( 6 )] . • Caspofungin acetate for Injection is contraindicated in patients with known hypersensitivity to any component of this product. ( 4 )

7 DRUG INTERACTIONS Cyclosporine : In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin acetate for injection. Caspofungin acetate for injection did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin acetate for injection and cyclosporine were co-administered. Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )]. Tacrolimus : For patients receiving Caspofungin acetate for Injection and tacrolimus, standard monitoring of tacrolimus trough whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Inducers of Hepatic CYP Enzymes Rifampin : Rifampin is a potent CYP3A4 inducer and concomitant administration with caspofungin acetate for injection is expected to reduce the plasma concentrations of caspofungin acetate for injection. Therefore, adult patients on rifampin should receive 70 mg of Caspofungin acetate for Injection daily and pediatric patients on rifampin should receive 70 mg/m 2 of Caspofungin acetate for Injection daily (not to exceed an actual daily dose of 70 mg) [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . Other Inducers of Hepatic CYP Enzymes Adults : When Caspofungin acetate for Injection is co-administered to adult patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg of Caspofungin acetate for Injection should be considered [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . Pediatric Patients : When Caspofungin acetate for Injection is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg/m 2 Caspofungin acetate for Injection (not to exceed an actual daily dose of 70 mg) should be considered [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary Based on animal data, Caspofungin acetate for Injection may cause fetal harm (see Data ) . There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with Caspofungin acetate for Injection use in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri- implantation loss, and incomplete ossification at multiple fetal sites when administered intravenously to pregnant rats and rabbits during organogenesis at doses up to 0.8 and 2 times the clinical dose, respectively ( see Data ). Advise patients of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In animal reproduction studies, pregnant rats dosed intravenously with caspofungin during organogenesis (gestational days [GD] 6 to 20) at 0.5, 2, or 5 mg/kg/day (up to 0.8 times the clinical dose based on body surface area comparison) showed increased resorptions and peri-implantation losses at 5 mg/kg/day. Incomplete ossification of the skull and torso and increased incidences of cervical rib were noted in offspring born to pregnant rats treated at doses up to 5 mg/kg/day. In pregnant rabbits treated with intravenous caspofungin during organogenesis (GD 7 to 20) at doses of 1, 3, or 6 mg/kg/day (approximately 2 times the clinical dose based on body surface area comparison), increased fetal resorptions and increased incidence of incomplete ossification of the talus/calcaneus in offspring were observed at the highest dose tested. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma. In peri- and postnatal development study in rats, intravenous caspofungin administered at 0.5, 2 or 5 mg/kg/day from Day 6 of gestation through Day 20 of lactation was not associated with any adverse effects on reproductive performance or subsequent development of first generation (F1) offspring or malformations in second generation (F2) offspring.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in detail in another section of the labeling: • Hypersensitivity [see Warnings and Precautions ( 5.1 )] • Hepatic Effects [see Warnings and Precautions ( 5.2 )] • Elevated Liver Enzymes During Concomitant Use with Cyclosporine [see Warnings and Precautions ( 5.3 )] • Adults : Most common adverse reactions (incidence 10% or greater) are diarrhea, pyrexia, ALT/AST increased, blood alkaline phosphatase increased, and blood potassium decreased. ( 6.1 ) • Pediatric patients : Most common adverse reactions (incidence 10% or greater) are pyrexia, diarrhea, rash, ALT/AST increased, blood potassium decreased, hypotension, and chills. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin acetate for injection cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults The overall safety of caspofungin acetate for injection was assessed in 1,865 adult individuals who received single or multiple doses of caspofungin acetate for injection: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 patients with invasive aspergillosis; and 394 individuals in phase I studies. In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus studies often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications. Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients In the randomized, double-blinded empirical therapy study, patients received either caspofungin acetate for injection 50 mg/day (following a 70 mg loading dose) or AmBisome ® (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the caspofungin acetate for injection and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia. Adverse reactions occurring in 7.5% or greater of the patients in either treatment group are presented in Table 2 . Table 2: Adverse Reactions Among Patients with Persistent Fever and Neutropenia Incidence 7.5% or Greater for at Least One Treatment Group Within any system organ class, individuals may experience more than 1 adverse reaction. * 70 mg on Day 1, then 50 mg once daily for the remainder of treatment; daily dose was increased to 70 mg for 73 patients. † 3 mg/kg/day; daily dose was increased to 5 mg/kg for 74 patients. Adverse Reactions Caspofungin Acetate for Injection * N=564 (percent) AmBisome † N=547 (percent) All Systems, Any Adverse Reaction 95 97 Investigations 58 63 Alanine Aminotransferase Increased 18 20 Blood Alkaline Phosphatase Increased 15 23 Blood Potassium Decreased 15 23 Aspartate Aminotransferase Increased 14 17 Blood Bilirubin Increased 10 14 Blood Magnesium Decreased 7 9 Blood Glucose Increased 6 9 Bilirubin Conjugated Increased 5 9 Blood Urea Increased 4 8 Blood Creatinine Increased 3 11 General Disorders and Admi…